Improving Prospects for Early Stage Lung Cancer Therapy

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Lung Cancer is the leading cause of cancer-related death in both men and women, and it is notoriously difficult to treat, but as research studies are showing, there are promising new treatments on the horizon. Our expert guest, Dr. Heather Wakelee, leads one such study testing new treatments for early stage lung cancer.

Dr. Wakelee is assistant professor of medicine in the Division of Oncology at Stanford University and a member of the Stanford Cancer Center, where she is the co-leader of the lung cancer disease management group. In this interview, Dr. Wakelee discusses advances in lung cancer research over the last five years and why she is excited about the future of treatment for early stage lung cancer.

Why Is Lung Cancer So Difficult to Find and Treat?

Dr. Wakelee:

I think one of the most important reasons that lung cancer is difficult to treat is that we are not yet very good at finding the disease when it's in an early stage, so most people are diagnosed after the cancer has already spread and is not curable. Also, in people where it is found early, even when the disease has been removed completely with surgery, the chance of it coming back is much higher in lung cancer than in many other types of cancer. And, finally, many of the treatments that we have such as chemotherapy, for reasons that we don't completely understand, are not as effective in lung cancer as they are in other cancers.

It might also be that we often don't have any symptoms until the cancer has gotten to be quite advanced. We don't have pain receptors in the lung that would tell us if something unusual is growing there. And we can't feel our lungs the way someone would, say, detect a breast cancer. So that might be part of it.

Types and Stages of Lung Cancer

Dr. Wakelee:

We tend to group lung cancer into two big groups. The first, which is actually the least common, is called small-cell lung cancer, and that's somewhere between 15 and 20 percent of all lung cancers. It's called small cell because that's how the cells look under the microscope, and that disease tends to be more aggressive in that it's almost never treated with surgery. Usually at the time it's found, it has either spread throughout the lungs or throughout the body, and we treat that with chemotherapy and radiation.

The other and much more common type of lung cancer we call non-small-cell lung cancer, again in contrast to the small cell. And within non-small cell lung cancer, there are these major groups: There is adenocarcinoma, which is the most common; squamous cell carcinoma; large cell carcinoma; and then an "other" category. Knowing the differences between those is becoming more important because some of our new treatments actually work differently in the different types of lung cancer.

About a third of patients are diagnosed in what we call early stage disease, and "early stage" means that it's a mass that's just in the lungs or a mass that's in the lung and has spread to some lymph nodes that are also in the lungs. In that situation, surgery is the most important part of treatment.

Another approximately one-third or so of patients have the disease where it's called "locally advanced," meaning that it has spread into the lymph nodes that are in the center part of the chest known as the mediastinum. When that happens, surgery alone isn't quite as helpful. It can be a part of treatment for some patients, but people in that situation need to have chemotherapy and usually radiation as well.

Close to 40 percent of patients are found [at the time of initial diagnosis] with advanced stage or stage IV disease, where it has spread either significantly throughout both lungs or outside of the lungs. In that situation, we talk mostly about systemic treatments like chemotherapy.

So with the numbers, stage I is a small mass that hasn't gone to any lymph nodes, stage II is in the lymph nodes in the lungs, stage III is in the lymph nodes in the mediastinum, and then stage IV is more distant spread.

Hope for Better Screening for Lung Cancer in the Future

Dr. Wakelee:

Screening methods have been an ongoing problem for a long time with lung cancer. Years ago, we were hopeful that by getting chest X-rays on a regular basis for people at high risk, such as those who were heavy smokers, we might be able to find the disease earlier. Or perhaps by having people cough up sputum, we could look in the sputum and find cancer cells and hopefully diagnose it earlier. Unfortunately when [clinical] trials were done looking at those techniques, there wasn't an overall improvement in survival between the groups that were getting more extensive screening and those that were not, and so those efforts were abandoned. Now we have CAT (computed axial tomography) scans, or CT scans, and there have been ongoing tests looking at getting CT scans on a regular basis for people who are at high risk of lung cancer.

There is controversy in that area right now. There was one trial known as the I-ELCAP (International Early Lung Cancer Action Program) study, which was published in the New England Journal of Medicine, which hinted that there was a benefit from CT screening in the group of patients that they studied, but there were some problems with the methodologies used in that study. There is another trial that has just completed enrollment that was sponsored by the National Cancer Institute. We don't know any information from that study yet. Hopefully in 2009 we will have some early results.

I think everyone who treats lung cancer patients is very, very hopeful that we will end up having a way of screening or finding the disease earlier. Where the controversy lies is in whether the CT screening is going to be enough. We are all hoping that maybe we will have blood tests that will help us also, and there is also the problem that we don't know who to screen. Most of the work has been focused on people with a history of heavy smoking, and that's certainly the biggest risk for lung cancer. But probably about 20 percent of women who get lung cancer have never smoked, and around 10 percent of men. So that's a substantial number of people who are at risk for lung cancer and would never be included in the screening. So that's another problem.

Surgery Plus Chemo for Early Stage Lung Cancer: A Cure for Some?

Dr. Wakelee:

Treatment for non-small cell lung cancer depends on stage. Patients with stage I and II cancers, the cancers that are still in the lungs, are mostly treated with surgery. And now additionally some of them get chemotherapy. Patients who have stage III lung cancer usually get some combination of chemotherapy, radiation and sometimes surgery. And people with the metastatic or stage IV lung cancer are treated mostly with the systemic treatment such as chemotherapy as well as some newer drugs, what we call targeted therapy. Those new targeted drugs work a little bit different than chemotherapy, but are also treatments that are either given by vein or as pills.

The biggest change in treatment recently was the introduction of chemotherapy after surgery, what we call adjuvant chemotherapy. That's something that we have known is helpful for many years for colon cancer and breast cancer, and everyone assumed it would help in lung cancer, but we really didn't have any good data from clinical trials until just the last few years. Several trials in the last five years have shown that by giving chemotherapy after surgery we were able to cure more people from their lung cancer. The first trial that came out was in 2003, and then in 2004 we had more trials and in 2005 another big study, all finally showing that by giving chemotherapy you could cure more people. That was really the biggest change.

Again, these results were for patients with early stage disease. Surgery alone, for patients who only have the cancer in the lung itself, can cure up to 70, maybe even 80 percent of patients who have really small tumors. Once the lymph nodes are involved, those cure rates drop down to maybe 50 to 60 percent [for surgery alone], depending on the size of the tumor and how many lymph nodes are involved. So we have a long way to go. It's very different than the cure rates of surgery alone for many breast cancers, say, as a comparison. The hope was that by adding the chemotherapy we could improve those cure rates.

What Other Factors Influence Lung Cancer Treatment Success?

Dr. Wakelee:

There are many factors that go into the decision of which patients should receive adjuvant chemotherapy. Part of it has to do with the tumor itself. With the studies that have been done so far, we know that chemotherapy is definitely helpful for patients who have what we call stage II, where the cancer has gone into lymph nodes within the lung. We know that it is also helpful for patients who have stage III lung cancer who had surgery. Sometimes we don't know that the lymph nodes in the center part of the chest, the mediastinum, have cancer in them until the surgery happens. And if that's found at the time of surgery, we know those patients are definitely helped with chemotherapy as well.

We don't know if patients with stage I lung cancer, the ones who don't have any lymph nodes involved, are helped as much with the chemotherapy. Perhaps patients with larger tumors are helped, but that is an area where some of the [clinical] trials have shown benefit, others have not. It has depended somewhat on the size of the tumor as well. So that's the tumor part.

And then the patients obviously factor into it considerably. People who recover very well from surgery clearly are going to be able to tolerate chemotherapy much better than people who have a long recovery time. So generally if someone has recovered pretty well within a month or two, that's someone we would consider offering chemotherapy. And if someone is still really having a hard time after two months, that's someone who is probably potentially going to be more harmed than helped by chemotherapy.

We also look at what other medical problems someone has. Age can also be a factor. Though in at least one of the trials that was recently reported, and it was strongly in favor of adjuvant chemotherapy, they defined older patients as those over age 65 and found that they had as much benefit as the younger patients. So it's not just the age though age can be an indication in some people of their other health status. I think for people who are over the age of 80, most would be pretty cautious about offering chemotherapy unless it's someone who is still jogging every day. But for people in their 70s, most who have lung cancer who are able to have a surgery are also going to be fit enough to tolerate chemotherapy.

Using More Than One Chemotherapy Drug to Treat Lung Cancer

Dr. Wakelee:

We tend to start chemotherapy about a month or two after the surgery has been completed and patients have had time to recover. Sometimes that's extended out to maybe three months after surgery, but further than that we don't know how much the chemotherapy might help. So that's the window. The treatments themselves last about three months. Most of the treatment is given one day intravenously every three weeks for a total of about four treatment cycles, so that ends up being about 12 weeks total.

Normally, one chemotherapy drug can work okay. But with lung cancer we know from patients who have advanced-stage disease that a combination of two drugs is better than one. And when you add a third traditional chemo drug, at least in advanced-stage lung cancer, that just adds side effects without improving the likelihood of it working. Now, that's different in different diseases, but in lung cancer it's specific.

Side Effects That Patients Can Expect with Chemotherapy

Dr. Wakelee:

Almost always in adjuvant (post-surgery) treatment, in the early stage, we use a drug called cisplatin (Platinol), and that's a chemotherapy drug that's been around for a long time that works right at the level of the DNA [deoxyribonucleic acid, the cell's genetic material]. It's often given in combination with a second drug, and there are several that have been used. The most common one used in adjuvant treatment is called vinorelbine (Navelbine), and that's a drug that's given also intravenously. They are both given together on the first day. The vinorelbine has to be given a little bit more frequently, so it's also given one week later.

Other drugs that we are looking at because we use them a lot in the metastatic setting are the taxanes, such as paclitaxel (Taxol) and docetaxel (Taxotere), and there is also a drug called gemcitabine (Gemzar). Again, those are all traditional chemotherapy drugs that at different levels work on DNA, though the taxanes are a little bit different in how they work, but it does get back down to the DNA.

The biggest side effect with all chemotherapy drugs, the traditional chemotherapy drugs, affects the bone marrow, which means that the levels of the white blood cells that usually fight infections go down. The red blood cells can also go down, making people anemic. The platelets, which are involved in clotting of blood, can also go down a little bit. And those effects all are what we call transient, meaning that they will happen for a week or so after the chemotherapy, and then it gets better on its own. Those are things that we can follow closely and usually treat pretty well. There are some drugs that can be given to counteract that as needed as well.

Chemotherapy also certainly has a reputation for causing nausea and vomiting, and those side effects are certainly a possibility. But very good drugs have been developed in the last few years to combat nausea and vomiting, so that's rarely as much of a problem as it has been in the past.

The cisplatin can affect the kidneys, and so we have to monitor kidney function and make sure people get a lot of fluids. But with doing that, we're usually pretty safe there. There are also effects on the nerves, what we call neuropathy - numbness and tingling in the hands and feet. Usually that also gets better though sometimes it does not completely get better after chemotherapy, and those are things that we look for as well. And then there are a handful of other problems that can happen that are much less common.

As someone is going through chemotherapy, we watch them very closely. We see people back at least every three weeks and talk about side effects and make adjustments as needed in the dosing if we need to do that.

Clinical Trial Aims to Prove Cancer Growth Can Be Blocked

Dr. Wakelee:

The way that we are able to move forward in treating lung cancer, really any cancer, is by doing clinical trials. And most of the trials are designed to look at how we move from what we know works, the standard of care, to the next level. So when I talk to my patients in clinic, I always talk to them about the fact that until five years ago we didn't know to even give chemotherapy at all in patients who had had their lung cancer removed until we had trials where people got chemotherapy or did not, and from that we learned that chemotherapy was helpful. Now that we know that the chemotherapy is helpful, all of the ongoing trials offer chemotherapy to everybody but now offer additional drugs to some patients on the trial, trying to see if the additional drugs can add to the chemotherapy.

The trial that I am running is looking at a drug known as bevacizumab. The trade name is Avastin, and that drug is an antibody. Antibodies are also given by vein, just like most of the chemotherapy. This antibody blocks what's known as VEGF, or vascular endothelial growth factor, and VEGF is a very important molecule in developing new blood vessels. How does that relate to cancer? Well, all cancer cells, in order for a tumor to grow to any particular size, have to get blood vessels to come into them. And so if you are able to block those new blood vessels from forming, that will block the cancer from growing.

In patients with metastatic lung cancer, we know that adding the bevacizumab to chemotherapy makes the chemotherapy work better. In that setting, it might work a little bit differently than actually blocking the blood vessel growth, but nonetheless we definitely know that it has worked in several trials. It increases the chances of the tumor shrinking, increases the time before the cancer starts to grow again and actually improved survival in at least one of big trials. So with that knowledge, it made sense to take bevacizumab and see if we could cure more people with it by bringing it into the early stage treatment setting, where patients have already had their cancers removed, many of them are cured, but we still need to improve those cure rates.

So in the trial I am running, everybody who enters the trial gets the standard chemotherapy we have been talking about with that cisplatin drug, and either vinorelbine or docetaxel or gemcitabine, and then half the patients on the trial also get bevacizumab.

How Biologic Treatments Stop 'Bad Behavior' of Cancer Cells

Dr. Wakelee:

Biologics differ from the traditional chemotherapy in that they are going after a different target that makes the cancer cell behave in a way we don't like. The traditional chemotherapies all focus on the making of new DNA, and if you block it, then the cancer cells die. The new biologics focus on something else that makes the cancer cell behave poorly, as I mentioned. Bevacizumab (Avastin) works at the level of the blood vessels. If we can block blood vessels from forming, that's going to make a tumor mass shrink and help the chemotherapy work better.

Some of the other new targeted agents such as erlotinib, commonly called Tarceva, work at the level of different proteins that are on the surface of cells, particularly cancer cells. That drug, erlotinib, goes after what's called the epidermal growth factor receptor or EGFR, and there are other agents that target that. There are also hundreds of new compounds being developed that focus on other proteins that are either more common in cancer cells or only seen in cancer cells. And therefore if you can block them, you are more likely to attack the cancer cell and not harm as many normal cells.

In this study, we are using bevacizumab because it was the first drug that was shown to really add to chemotherapy in metastatic disease. There had been dozens of trials looking at chemotherapy with or without new drug X, Y or Z, and up until bevacizumab none of them had shown an improvement in survival versus the chemotherapy by itself. So when the study came out showing that bevacizumab was able to improve survival when added to chemotherapy for patients with metastatic disease - not curing, but helping people live longer - it made sense to then take that drug and bring it into the early stage disease where we were hoping we could cure more people.

Additionally, because of how the drug works by blocking blood vessel growth, the hope is that it's going to work even better in the situation where you have just a few floating tumor cells that escaped at the time of surgery or before the surgery and are hanging out in the body. If we can stop them from growing and pulling in blood vessels to divide and then become a big tumor mass, then hopefully we will be able to cure more people that way.

Mixed Results on Biologics Depending on the Lung Cancer Stage

Dr. Wakelee:

We don't have a lot of data yet on biologics for treating early stage lung cancer. The closest we have is a trial in patients with stage III disease who had the involvement in the center part of the chest, the mediastinum. Those patients were treated with chemotherapy and radiation, and then half of them got a biologic known as gefitinib (Iressa), which is similar to erlotinib, and half of them got just a placebo pill. And in that study, for reasons we don't understand, the patients getting the gefitinib didn't do as well as those who weren't getting it. So that certainly is a word of caution and another reminder of why it's so important for us to do the clinical trials. We can't assume something is going to work in a different stage of disease just because we know it works in metastatic disease.

However, I am very, very hopeful that the treatments that we are looking at with bevacizumab, a vaccine trial being looked at in early stage disease and an ongoing adjuvant trial with erlotinib will all hold promise. I am obviously biased towards the bevacizumab, but I think that there is a lot of room for hope that with those we will be able to improve cure rates even further.

Participating in Clinical Trials for Early Stage Lung Cancer

Dr. Wakelee:

Our study is open to anybody who has a lung cancer that has been completely removed with surgery. It's very important that we know the stage of the patient, which means that if a patient is looking at having a surgery, they need to check with the surgeons that the lymph nodes that are in that mediastinum are sampled at the time of surgery, because that helps us know what stage they are.

So anybody who has a stage I, II or III lung cancer, is eligible for the trial assuming that they are otherwise in good shape. People who have significant heart disease, we don't allow on the trial because if you think about it, the bevacizumab works by blocking blood vessel formation. If you have heart problems, you probably need a little bit more blood vessel formation, especially around the heart. We don't want to put people at risk. Also, in anyone with history of a stroke, there is the same potential concern. We don't want to put anybody on trial that's going to be at higher risk because they have a history of a stroke. But otherwise patients with stage I tumors that are at least four centimeters in size - and that is because of the earlier studies showing that we weren't helping the patients with smaller tumors as much - and anybody with stage II and stage III-A lung cancer.

It's always best to talk to your doctor, and that can be talking to the surgeon but almost everybody with a resected lung cancer should meet with a medical oncologist. They might choose not to get treatment at all, but at least talk with the people who actually give the treatment to learn more about it. Most physicians in this country are aware of this trial. We have close to 700 sites throughout the country that are open to enrollment for patients. There is a lot of information available on a Web site run by the National Cancer Institute, called clinicaltrials.gov. To look up our particular trial, search for the name of the study, E1505.

The Benefits and Risks of Participating in a Clinical Trial

Dr. Wakelee:

The benefits of participating in trials are the ability to have access to drugs that might not be available any other way. Also, the patients on clinical trials are watched a little bit more closely. And in addition to your doctor and the nurses, you also have the people who are working on the trial helping you, which can be a very good thing. I think that the importance of feeling like you are actually focusing on helping yourself but are doing something to help others who are suffering with the same disease really shouldn't be downplayed. That's pretty important.

Risks? Well, with any treatment for cancer there are risks, unfortunately. We haven't yet come up with treatments that don't have any side effects, and with the clinical trials sometimes we don't know. We don't know all of the potential side effects of a drug fairly early in development. There is a lot of uncertainty. And we also don't always know that the treatment is going to be better than the standard of care.

Trials are designed very carefully to make sure that people are offered at least the standard, and we try to design them as you are either going to get the standard of care, which you would get if you weren't on the trial, or you are going to get the standard of care plus something else. Now, occasionally if we are in a situation where there is no approved agent, where there is nothing that we know helps, then there are still some placebo-controlled trials, but that's not usually the situation. If you are going into a clinical trial, you will know if you are on a study that involves a placebo or not. That's one of the important things to talk to your doctor about if you are looking at a study.

Lung cancer remains a very challenging disease, but we are definitely making progress. In the last five years, we have seen development of many new targeted agents for advanced-stage disease. We have also seen the onset of a time where we are able to use adjuvant therapy, and we are being able to focus now on treating people more individually. Those are areas of very exciting research. I think that as we continue to move forward, the ongoing clinical trials are really leading the way in helping us know where to go.

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